Development of a Predictive Response Signature to Anti-Thymocyte Globulin in Type 1 Diabetes

1 型糖尿病抗胸腺细胞球蛋白预测反应特征的开发

• 批准号: 10450675
• 负责人: Laura Jacobsen
• 金额: $ 12.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450675
• 关键词: Algorithms; Antithymoglobulin; Area Under Curve; Autoimmune Diseases; Beta Cell; Big Data Methods; Biological Assay; Biological Markers; C-Peptide; CD4 Positive T Lymphocytes; CSF3 gene; Career Choice; Cell Death; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Complex; Coupled; Data; Defect; Development; Development Plans; Disease; Dose; Endocrinologist; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Florida; Flow Cytometry; Frequencies; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Glycosylated hemoglobin A; Goals; Heterogeneity; Human; Immune; Immune Tolerance; Immunology procedure; Immunophenotyping; Immunotherapy; In Vitro; Individual; Institutes; Insulin-Dependent Diabetes Mellitus; Intervention; Intervention Trial; Knowledge; Manuscripts; Measures; Mediating; Methodology; Methylation; Mission; Outcome Assessment; Outcome Measure; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Physicians; Placebos; Play; Preparation; Production; Regulatory T-Lymphocyte; Research Personnel; Role; Sampling; Scientist; Structure of beta Cell of islet; Subgroup; Surface; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transcript; United States National Institutes of Health; Universities; Work; adaptive immune response; arm; career; career development; clinical care; clinical efficacy; clinical trial enrollment; differential expression; epigenetic profiling; exhaust; exhaustion; immune function; immunological intervention; immunomodulatory therapies; immunotherapy clinical trials; immunotherapy trials; improved; in vitro Model; in vitro testing; in vivo; in vivo evaluation; individual patient; innovation; insulin dependent diabetes mellitus onset; methylome; next generation; peripheral blood; personalized care; personalized therapeutic; precision medicine; predicting response; predictive marker; preservation; primary outcome; prospective; response; response biomarker; responsible research conduct; side effect; single cell analysis; single-cell RNA sequencing; skills; success; transcriptome; transcriptomics; treatment optimization; treatment response

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is caused by T cell-mediated destruction of pancreatic β-cells. A combination of genetic and environmental factors contributes to this complex autoimmune disease. T1D is without any durable disease- altering therapies though several clinical trials in recent-onset T1D have demonstrated transient β-cell preservation. Anti-thymocyte globulin (ATG), which at low doses can modulate T cells and other adaptive/innate immune cells, is one such immunomodulatory therapy. Compared to placebo, ATG, given in a low dose over 2 days, demonstrated more than 40% higher preservation of C-peptide and nearly 1% lower HbA1c 2 years after therapy in recent-onset T1D subjects. However, within successful T1D immunotherapy trials like low dose ATG, there are clinical “responders” (those who produce significantly more C-peptide in response to therapy) and “nonresponders.” The field of T1D lacks an ability to determine these clinical responders prior to clinical trial enrollment and drug administration, thus exposing some individuals to ineffective interventions with considerable side effect profiles. Utilizing samples from the NIH-funded TrialNet Low-dose ATG in Recent-Onset T1D clinical trial (TN19), the objective of this proposal is to develop a response signature to ATG for use in future clinical trial enrollment criteria and eventual clinical care. The objective that transcriptome, methylome and immunophenotyping differences can identify a responder signature to ATG in T1D will be tested. Specifically, Aim 1 will develop a biomarker of response using a unique in vitro model of ATG stimulation in TN19 baseline clinical trial samples. The hypothesis being that innate and adaptive-specific genes will demonstrate differential expression and methylation profiles with distinct immune phenotypes in clinical responders compared to nonresponders following in vitro ATG stimulation. This is assessing the methodology of performing in vitro pre- enrollment testing of a subject’s peripheral blood to determine their likelihood of response. Aim 2 will identify the mechanisms of clinical efficacy through innovative single cell RNA sequencing, T cell receptor (TCR) α/β pairing, TCR immunosequencing, and surface marker expression. In addition, the function of immune subpopulations known to play a key role in immune tolerance (regulatory T cells and exhausted T cells) will add to the mechanistic determination of ATG efficacy. This work may facilitate prospective personalized therapeutic planning for individual patients or precision medicine-directed clinical trial enrollment criteria. These biomarkers would improve responder rates and reduce exposure of nonresponders to side effects. My career goal of developing predictive biomarkers for T1D immunotherapy clinical trials will be advanced by this proposal. Highly valued skills set forth in the career development plan aim to promote further independence as an investigator and include training in 1) immunological assays, 2) big data analytics, 3) responsible conduct of research, and 4) clinical trial design. The collaborative rapport and mission of training the next generation of investigators across all institutes and departments of the University of Florida provide an ideal environment for career success.

项目摘要/摘要 1型糖尿病（T1D）是由T细胞介导的胰腺β细胞破坏引起的。 环境因素有助于自身免疫性疾病。 在近期运算中的严重程度clials的改变已显示出瞬时细胞 保存。 免疫细胞是一种与安慰剂相比，ATG的一项检查。 几天，在2年后，显示C肽的保存率高超过40％，HBA1C降低了近1％ 但是，在成功的T1D免疫疗法试验中，近期发作的T1D受试者（例如低剂量ATG） 有临床“响应者” “无响应者。” T1D领域缺乏确定这些临床反应的能力 入学和药物管理，从而使某些人暴露于效率低下 副作用轮廓。 试验（TN19），该提案的目的是为ATG开发响应签名，以供将来的Cleare试验 入学标准和最终的临床护理。 免疫表型差异可以通过测试来识别T1D中对ATG的响应。 AIM 1将使用TN19基线中ATG刺激的独特体外模型发展响应的生物标志物 临床试验样本。 与 在体外ATG刺激之后的无响应者正在评估进行体外前的方法 对受试者的外围血的注册测试确定AIM 2的可能性。 通过创新的单一Celle Celle细胞RNA测序，TCELL受体（TCR）α/β配对的临床机制， TCR imunosequencing和表面标记表达。 已知在免疫耐受性中发挥关键作用 ATG疗效的机械确定可能有助于预期的个性化治疗 为单个患者或精密医学临床试验标准 将提高响应率，并减少我的职业目标。 开发用于T1D免疫疗法的预测生物标志物遗嘱遗嘱遗嘱。 职业发展计划中提出的有价值的技能旨在促进作为本节目的进一步独立性 并包括1）免疫学分析中的培训，2）大数据分析，3）负责任的研究， 4）临床试验设计。 在佛罗里达大学的所有研究所和系中，为护理职业成功提供了理想的环境。